ABSTRACT Obesity prevalence continues to increase worldwide; 69% of U.S. adults are overweight or obese. Despite advances in understanding obesity pathophysiology, weight loss with current non-surgical treatments (diet and medications) is highly variable, and predictors of weight loss with obesity pharmacotherapy are unknown. In studies funded by RO1-DK67071 in 509 participants, obesity was associated with greater fasting gastric volume, accelerated gastric emptying (solids and liquids), lower postprandial peak plasma PYY, and greater calories consumed to achieve satiation (volume to fullness) and to evoke satiety with an ad-libitum meal. We showed that a short-acting GLP-1 agonist, exenatide, 5g, SQ, BID for 30 days, delays gastric emptying and induces weight loss. Thus, quantitative gastrointestinal (GI) traits are associated with higher BMI, distinguish obesity phenotypes, and may predict efficacy of obesity drug therapy. In the R56-DK67071-funded pilot randomized, placebo-controlled trial of the longer-acting GLP-1 agonist, liraglutide, 3mg, SQ daily, we showed: (a) feasibility to recruit and randomize, over 8 months, 30 patients into a 4-month study (only 2 dropouts on treatment, to date); (b) safety data in all 30 randomized patients; (c) baseline quantitative traits of gastric emptying of solids and liquids, fasting and postprandial gastric volumes; satiation and satiety data; postprandial plasma incretins (GLP-1 and PYY) in all randomized patients; (d) gastric emptying data at fully escalated dose of liraglutide (weeks 5-6) in 30 patients; (e) repeat measurement (as in c) of quantitative traits at 16 weeks' treatment in 28 patients; (f) monthly weight data for duration on treatment in 28 patients. Our overall hypothesis is that weight loss with pharmacological agents may be individualized, based on specific abnormalities in quantitative GI traits. We propose a randomized, controlled clinical and pharmacodynamics trial, using a 2-treatment stratified design, to assess the hypothesis that a quantitative trait (gastric emptying rate) can impact the weight loss response among overweight (BMI >27kg/m2 plus obesity co- morbidities) or obese (BMI >30kg/m2) patients to treatment with the FDA-approved GLP-1 receptor agonist, liraglutide (dose escalated to maximum of 3mg, SQ, per day for 12 weeks) compared to placebo. Effects will be compared for those with baseline accelerated in comparison with normal gastric emptying. Our aims are: first, to assess the effects of liraglutide, 3mg/day, on gastric motor functions, satiation, satiety, weight loss and incretins; and second, to appraise the association of baseline accelerated gastric emptying on weight loss in response to liraglutide treatment. By measuring quantitative Gl traits at baseline and after 12 weeks of liraglutide treatment, we shall further understand the mechanism of action of this GLP-1 agonist. Significance: Our study addresses the treatment of obesity, introducing an era of individualizing drug therapy for obesity based on quantitative biomarkers. Therefore, it addresses an important public health challenge.